Regulation of virus release by the macrophage-tropic human immunodeficiency virus type 1 AD8 isolate is redundant and can be controlled by either Vpuor Env

The human immunodeficiency virus type 1 (HIV-1) Vpu and Env proteins are ex pressed from a bicistronic mRNA. To address the biological significance of the coordinated expression of vpu and env, we compared the relative effects on particle release of HIV-1 isolates containing an intact vpu gene or car rying point mutations in its initiation codon or internal deletions, respec tively. We found that the primary AD8 isolate, which is unable to express v pu due to a mutation in its translation initiation codon, was able to repli cate in primary macrophages and peripheral blood mononuclear cells with eff iciency similar to that of an isogenic variant expressing Vpu. Interestingl y, AD8 lacking a vpu initiation codon produced higher levels of Env protein than its Vpu-expressing isogenic variant. In contrast, disabling Vpu witho ut removing the vpu initiation codon did not alter Env expression but signi ficantly reduced virus production. AD8 Env when provided in trans was capab le of enhancing release not only of AD8 particles but also of viruses of th e T-cell-tropic NL4-3 isolate. We conclude that AD8 Env encodes a Vpu-like activity similar to that previously reported for HIV-2 Env proteins and is thus able to augment virus secretion. When expressed at elevated levels, i. e., following mutation of the vpu initiation codon, AD8 Env was able to com pensate for the lack of Vpu and thereby ensure efficient virus release. Thu s, the ability to regulate virus release is redundant in AD8 and can be con trolled by either Vpu or Env. Since Vpu controls several independent functi ons, including CD4 degradation, our results suggest that some HIV-1 isolate s may have evolved a mechanism to regulate Vpu activity without compromisin g their ability to efficiently replicate in the host cells.